We propose this renewal of RO1 HL67406 "Prediction and Progression of Carotid Artery Disease" (CAAD). CAAD is an important risk factor for stroke, the third leading cause of death in the U.S., and its risk factors overlap significantly with those of coronary artery disease, the major cause of death. Strong evidence of an important role of lipoprotein and vessel wall oxidation in vascular disease has emerged from both animal and human studies. As outlined in the Progress section, this multidisciplinary project has established that low paraoxonase (PON1) activity is predictive of CAAD, identified additional functional variation in PON1, evaluated the role of PON1 functional genotype and haplotypes effects in CAAD progression and prediction, and examined the linkage disequilibrium structure of PON1 and its effects on outcome prediction. We propose to continue and expand upon these productive studies, expanding our analyses to all common variation in a group of 29 low density lipoprotein and vessel wall oxidation pathway genes using a tagSNP approach as well as to 4 oxidative phenotypes that have been implicated in vascular disease prediction by ourselves or others. These phenotypes are LDL susceptibility to oxidation, PON1 activity, myeloperoxidase protein level, and glutathione peroxidase level, 3 of which at least preliminarily predict case status in our cohort. In addition to examining these factors in cases and controls, we will examine them in a unique 36 month longitudinal carotid magnetic resonance imaging (MR) progression dataset. This will allow us to evaluate whether these oxidative loci and phenotypes impact progression, as well as risk, of disease. Major aims are: Aim 1: Identify common genetic variation in 29 oxidative loci that predict either CAAD case-control status or progression of CAAD measured by magnetic resonance imaging (MR). Aim 2: Investigate the role of oxidative phenotypes myeloperoxidase, glutatione peroxidase, LDL susceptibility to ex vivo oxidation, and PON1 activity in the prediction of CAAD case-control status and progression measured by MR. Aim 3: Pathway evaluation of oxidative loci and phenotypes in prediction of CAAD.